EP2215094B1 - Composés hétérocycliques à teneur en n - Google Patents

Composés hétérocycliques à teneur en n Download PDF

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EP2215094B1
EP2215094B1 EP08849455.4A EP08849455A EP2215094B1 EP 2215094 B1 EP2215094 B1 EP 2215094B1 EP 08849455 A EP08849455 A EP 08849455A EP 2215094 B1 EP2215094 B1 EP 2215094B1
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EP2215094A1 (fr
EP2215094A4 (fr
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David Gerard Bourke
Christopher John Burns
Anthony Nicholas Cuzzupe
John Thomas Feutrill
Marcel Robert Kling
Tracy Leah Nero
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YM Biosciences Australia Pty Ltd
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YM Biosciences Australia Pty Ltd
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Priority to SI200831574A priority Critical patent/SI2215094T1/sl
Priority to EP15192182.2A priority patent/EP3109249A1/fr
Publication of EP2215094A1 publication Critical patent/EP2215094A1/fr
Publication of EP2215094A4 publication Critical patent/EP2215094A4/fr
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    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to N-containing heterocyclic compounds that are inhibitors of protein kinases including JAK kinases.
  • the compounds are selective for JAK1, JAK2, JAK3 or TYK2 kinases and combinations thereof such as JAK1 and JAK2.
  • the kinase inhibitors can be used in the treatment of kinase associated diseases such as immunological and inflammatory diseases including organ transplants; hyperproliferative diseases including cancer and myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases.
  • JAKs are kinases which phosphorylate a group of proteins called Signal Transduction and Activators of Transcription or STATs. When phosphorylated, STATs dimerize, translocate to the nucleus and activate expression of genes which lead to, amongst other things, cellular proliferation such as proliferation of endothelial cells and smooth muscle cells, and cause hypertrophy of cardiac myocytes.
  • inhibitors of JAKs could be used for immunological and inflammatory diseases including organ transplants, asthma and chronic obstructive pulmonary disease (COPD) as well as autoimmune diseases such as systemic lupus erythematosus, mixed connective tissue disease, scleroderma, autoimmune vasculitides, multiple sclerosis, rheumatoid arthritis, Crohn's disease, Type I diabetes and autoimmune thyroid disorders.
  • autoimmune diseases such as systemic lupus erythematosus, mixed connective tissue disease, scleroderma, autoimmune vasculitides, multiple sclerosis, rheumatoid arthritis, Crohn's disease, Type I diabetes and autoimmune thyroid disorders.
  • JAK family of protein tyrosine kinases in the cytokine dependent regulation of both proliferation and end function of several important cell types indicates that agents capable of inhibiting the JAK kinases are useful in the prevention and chemotherapeutic treatment of disease states dependent on these enzymes.
  • Potent and specific inhibitors of each of the currently known four JAK family members will provide a means of inhibiting the action of the cytokines that drive immunological and inflammatory diseases, such as those discussed above.
  • JAK inhibitors treatment of hyperproliferative disorders such as cancers including multiple myeloma; prostate, breast and lung cancer; gastric cancer; Hodgkin's Lymphoma; B-cell Chronic Lymphocytic Leukemia; metastatic melanoma; glioma; and hepatoma.
  • JAK kinase inhibitors for the treatment of viral diseases and metabolic diseases is indicated.
  • Potent inhibitors of JAK2 in addition to the above, will also be useful in vascular disease such as hypertension, hypertrophy, cardiac ischemia, heart failure (including systolic heart failure and diastolic heart failure), migraine and related cerebrovascular disorders, stroke, Raynaud's phenomenon, POEMS syndrome, Prinzmetal's angina, vasculitides, such as Takayasu's arteritis and Wegener's granulomatosis, peripheral arterial disease, heart disease and pulmonary arterial hypertension.
  • JAK2 inhibitors will also be useful in myeloproliferatve disorders (MPDs) such as polycythemia vera (PV).
  • MPDs myeloproliferatve disorders
  • PV polycythemia vera
  • JAK1 and JAK2 will be useful in the treatment of cancers including multiple myeloma; prostate, breast and lung cancer; Hodgkin's Lymphoma; B-cell Chronic Lymphocytic Leukemia; metastatic melanoma; multiple myeloma; gastric cancer; glioma; and hepatoma.
  • JAK3 Potent and specific inhibitors of JAK3 will be useful as immunosuppressive agents for, amongst others, organ transplants, and immunological and inflammatory diseases such as asthma and chronic obstructive pulmonary disease as well as autoimmune diseases such as systemic lupus erythematosus, mixed connective tissue disease, scleroderma, autoimmune vasculitides, multiple sclerosis, rheumatoid arthritis, Crohn's disease, Type I diabetes and complications from diabetes, metabolic diseases, and other indications where immunosuppression may be desirable.
  • specific inhibitors of JAK3 may find application for therapeutic treatments for proliferative diseases such as leukaemia and lymphoma where JAK3 is hyperactivated.
  • JAK3 expression appears to be limited to hematopoetic cells. This is consistent with its essential role in signalling through the receptors for IL-2, IL4, IL-7, IL-9 and IL-15 by non-covalent association of JAK3 with the gamma chain common to these multichain receptors.
  • Males with X-linked severe combined immunodeficiency (XSCID) have defects in the common cytokine receptor gamma chain (gamma c) gene that encodes a shared, essential component of the receptors of interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15.
  • XSCID X-linked severe combined immunodeficiency
  • Prolonged immunomodulation through inhibition of JAK3 signalling should have great therapeutic potential for chronic diseases as long as JAK3 inhibition was achieved selectively and not accompanied by inhibition of other kinase-dependent signalling processes.
  • the high degree of sequence identity held in common by members of the JAK family of kinases raises the possibility that a compound which inhibits JAK3 would also inhibit other members of the family with detrimental long term consequences.
  • prolonged inhibition of JAK2 is likely to lead to erythropenia and thrombocytopenia, since the receptors for both erythropoietin and thrombopoietin use only JAK2 for intracellular transmission of signals.
  • Compounds of the present invention may also be useful in targeting other kinases of therapeutic relevance, such as the Aurora kinases.
  • the Aurora family of serine/threonine protein kinases are critical for the proper regulation of mitosis. Mammals express three Aurora kinase paralogs, and at least two Aurora kinases (Aurora A and B) are commonly overexpressed in human tumours including breast, lung, colon, ovarian, and pancreatic cancers.
  • the Aurora A gene is amplified in many tumours, indicating that overexpression of Aurora A may confer a selective advantage for the growth of these tumours.
  • kinases which may be useful therapeutic targets include CK2, TBK1, NEK9, LCK , ACK1, p38 kinase, FAK, CAK, CDK1, 2 and 4, GSK-3 ⁇ , Abl, PDGF-R, PLK1, PLK2, PLK3, PYK2, c-Kit, NPM-ALK, Flt-3, c-Met, KDR, EGFR, TIE-2, VEGFR-1,VEGFR-3, c-SRC, LCK, HCK, LYN, FYN and YES.
  • JAK1, JAK2, JAK3 or TYK2 inhibitors or combinations thereof, and aurora kinase inhibitors for use in treatment of kinase associated diseases such as immunological and inflammatory diseases including organ transplants; hyperproliferative diseases including cancer and myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases, include designing compound with appropriate specificity which also has good drug likeness properties.
  • the compounds of formula I are kinase inhibitors, preferably JAK inhibitors, more preferably JAK1, JAK2, JAK3 or TYK2 inhibitors. These compounds are useful in the treatment of a kinase associated disease, preferably a JAK kinase or aurora kinase associated disease such as immunological and inflammatory diseases; hyperproliferative diseases including myeloproliferative diseases; vascular diseases; viral diseases and metabolic diseases.
  • a kinase inhibitor comprising the compound formula I defined above.
  • the compounds of formula I preferably act as selective JAK2 inhibitors, selective JAK3 inhibitors or selective JAK1 and JAK2 inhibitors.
  • the compound of formula I may also be administered in the form of a pharmaceutical composition together with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising the compound of formula I defined above and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition also comprises one or more additional therapeutic agents.
  • the compound of formula I may be contained within or attached to an implant, such as a drug eluting stent.
  • an implant such as a drug eluting stent.
  • the compound when the compound is used for the treatment of pulmonary arterial hypertension (PAH), the compound may be contained within or attached to a pulmonary artery stent, which may act locally, or be released from the stent into the pulmonary circulation where the compound exerts its therapeutic activity in the pulmonary vasculature.
  • PAH pulmonary arterial hypertension
  • an implant which comprises the compound of formula I defined above.
  • a compound of formula I or a pharmaceutical composition defined above for use in a method for the treatment of a kinase associated disease such as immunological and inflammatory diseases including organ transplants; hyperproliferative diseases including cancer and myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases which comprises administering a therapeutically effective amount of the compound of formula I or a pharmaceutical composition defined above to a subject in need thereof.
  • a kinase associated disease such as immunological and inflammatory diseases including organ transplants; hyperproliferative diseases including cancer and myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases which comprises administering a therapeutically effective amount of the compound of formula I or a pharmaceutical composition defined above to a subject in need thereof.
  • kinase associated disease such as immunological and inflammatory diseases including organ transplants; hyperproliferative diseases including cancer and myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases.
  • a compound of formula I or a pharmaceutical composition as defined above for use in a method for the treatment of a kinase associated disease such as immunological and inflammatory diseases including organ transplants; hyperproliferative diseases including cancer and myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases.
  • a kinase associated disease such as immunological and inflammatory diseases including organ transplants; hyperproliferative diseases including cancer and myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases.
  • a kinase associated disease such as immunological and inflammatory diseases including organ transplants; hyperproliferative diseases including cancer and myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases.
  • a compound of formula I defined above for use in a method of inhibiting a kinase in a cell comprising contacting the cell with the compound of formula I defined above.
  • the present invention relates to compounds of formula I that inhibit kinases, in particular JAK kinases such as JAK1, JAK2, JAK3 or TYK2 kinases or aurora kinases and are useful in the treatment of kinase associated diseases such as immunological and inflammatory diseases including organ transplants; hyperproliferative diseases including cancer and myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases.
  • JAK kinases such as JAK1, JAK2, JAK3 or TYK2 kinases or aurora kinases
  • kinase associated diseases such as immunological and inflammatory diseases including organ transplants; hyperproliferative diseases including cancer and myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases.
  • the present invention further relates to salts and/or steroismers of a compound of formula I; isomers and/or prodrugs of a compound of formula I are disclosed herein: wherein
  • a preferred embodiment is the compound of formula I wherein Z, A, B, R, R 1 , and m are as defined above.
  • a preferred substituted or unsubstituted 5 or 6 membered aryl for R is phenyl unsubstituted or substituted with at least one of NR 2 R 3 , NR 2 COR 3 , substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted 5 to 8 membered heterocyclyls having up to 3 heteroatoms selected from N, O, S and SO 2 , SO 2 NR 2 R 3 , NR 2 CONR 2 R 3 , NR 2 SO 2 R 3 , R 2 OH, R 2 NHCO 2 R 3 , OCF 3 , CONR 2 R 3 or substituted or unsubstituted C 1 - 6 alkyl.
  • Preferred substituted or unsubstituted 5 to 9 membered heterocyclyls having up to 3 heteroatoms selected from N, O, S and SO 2 for R are saturated or unsaturated 5 to 9 membered heterocyclyls having 1 to 2 N atoms such as pyrazolyl, pyridinyl, 1,2,3,6-tetrahydro-pyridinyl and pyrimidinyl or saturated or unsaturated 5 to 9 membered heterocyclyls having 1 to 2 O atoms such as benzoxadiazolyl, each of which may be substituted with at least one of C 1-6 alkoxy, CO 2 R 3 or NR 2 R 3 .
  • R 1 is preferably independently selected from H, halogen, substituted or unsubstituted C 1-6 alkenyl, substituted or unsubstituted C 2-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, OH, halogen, NO 2 , NR 2 R 3 , NR 2 COR 3 , CO 2 R 3 , SO 2 R 3 , NR 2 SO 2 R 3 , substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 5 or 6 membered aryl and substituted or unsubstituted 5 to 8 membered saturated or unsaturated heterocyclyl having up to 3 heteroatoms selected from N, O, S and SO 2 .
  • Preferred substituted or unsubstituted 5 to 8 membered heterocyclyls having up to 3 heteroatoms selected from N, O, S and SO 2 for R 1 are 5 or 6 membered saturated or unsaturated heterocyclyls having up to 3 heteroatoms selected from N, O and S such as morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomopholino-1,1-dioxide, NR 2 -piperazine, 4-hydroxy piperidine, 3-hydroxy pyrrolidine, 3-hydroxypyrrole, piperidine and pyrrolidine.
  • one of A-R 1 and a substituent of R is preferably selected from groups that can react reversibly or irreversibly with a thiol moiety such as the thiol groups of the Cys963 residue of JAK3. Examples of such groups include Michael acceptors.
  • Michael acceptors are ⁇ , ⁇ -unsaturated carbonyl or thiocarbonyl compounds and selected examples are shown below.
  • ketones aldehydes, ⁇ -acyloxy ketones, ⁇ -phenoxy ketones, halo methyl ketones, maleimides, nitriles, 1,2,4-thiadiazoles, 2-vinyl oxazoles. 2-alkynyl-oxazoles, keto-oxazoles, cyclic disulfides, epoxides and O-acyl hydroxamates.
  • C 1-6 alkyl refers to straight chain or branched chain hydrocarbon groups having from 1 to 6 carbon atoms. Examples include ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl.
  • C 1-6 alkylene refers to the divalent equivalent of "C 1-6 alkyl” defined above.
  • C 2-6 alkenyl refers to straight chain or branched chain hydrocarbon groups having at least one double bond of either E or Z stereochemistry where applicable and 2 to 6 carbon atoms. Examples include vinyl, 1-propenyl, 1- and 2-butenyl and 2-methyl-2-propenyl.
  • C 2-6 alkynyl refers to straight chain or branched chain hydrocarbon groups having at least one triple bond and 2 to 4 carbon atoms. Examples include ethynyl, 1- or 2-propynyl, 1-, 2- or 3- butynyl and methyl-2-propynyl.
  • C 3-6 cycloalkyl refers to non-aromatic cyclic hydrocarbon groups having from 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • aryl refers to single, polynuclear, conjugated or fused residues of aromatic hydrocarbons. Examples include phenyl, biphenyl, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenxanthracenyl and phenanthrenyl. 5- or 6- membered aryls such as phenyl are preferred.
  • heterocyclyl refers to saturated or unsaturated, monocyclic or polycyclic hydrocarbon groups containing at least one heteroatom atom selected from the group consisting of N, O, S and SO 2 .
  • Suitable heterocyclyls include N-containing heterocyclic groups, such as, unsaturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl, piperidino or piperazinyl; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indolizinyl, pyrrolinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl or tetra
  • Preferred heterocyclyls are morpholino, thiomorpolino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, NR 2 -piperazine, 4-hydroxy piperidine, 3-hydroxy pyrrolidine, 3-hydroxypyrrole or piperidine.
  • halogen refers to fluorine, chlorine, bromine and iodine, preferably fluorine.
  • substituted or substituted refers to a group that may or may not be further substituted with one or more groups selected from C 1-6 alkyl, Si(C 1-6 alkyl) 3 , C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heterocycylyl, halo, haloC 1-6 alkyl, haloC 3-6 cycloalkyl, haloC 2-6 alkenyl, haloC 2-6 alkynyl, haloaryl, haloheterocycylyl, hydroxy, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, aryloxy, heterocyclyloxy, carboxy, haloC 1-6 alkoxy, haloC 2-6 alkenyloxy, haloC 2-6 alkynyloxy, haloaryloxy, nitro, nitroC 1-6 1-6
  • Preferred optional substituents are selected from the group consisting of C 1-4 alkyl, Si(C 1-6 alkyl) 3 , C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heterocycylyl, halo, hydroxy, C 1-4 alkoxy, aryloxy, carboxy, amino, arylacyl, heterocycylylacyl, acylamino, acyloxy, arylsulfonyl and cyano.
  • the compounds of the invention may also be prepared as salts which are pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium; acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, orthophosphoric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids; or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulfonic, trihalomethanesulfonic, toluenesulfonic,
  • the salts may be formed by conventional means, such as by reacting the free base form of the compound with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
  • the compound can be used as a purified enantiomer or diastereomer, or as a mixture of any ratio of stereoisomers. It is however preferred that the mixture comprises at least 70%, 80%, 90%, 95%, 97.5% or 99% of the preferred isomer.
  • prodrugs of the compounds of formula I For example, compounds of formula I having free amino, amido, hydroxy or carboxylic acid groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy and carboxylic acid groups of compounds of the invention.
  • the amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
  • Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of compounds of the present invention through the carbonyl carbon prodrug sidechain.
  • Prodrugs also include phosphate derivatives of compounds (such as acids, salts of acids, or esters) joined through a phosphorus-oxygen bond to a free hydroxyl of compounds of formula I.
  • Prodrugs may also include N-oxides, and S-oxides of appropriate nitrogen and sulfur atoms in formula I.
  • This invention also encompasses drugs of compounds of the invention for use in methods of treating or preventing disorders that can be treated or prevented by the inhibition of protein kinases, such as JAK or aurora kinases comprising administering drugs of compounds of the invention.
  • protein kinases such as JAK or aurora kinases
  • the first step of the process typically involves a nucleophilic aromatic substitution reaction of the dihalogenated heterocycle with a suitable amine.
  • the nucleophilic aromatic substitution is typically carried out by addition of the amine to the dihalogenated heterocycle in a solvent such as ethanol, n-propanol, isopropanol, tert-butanol, dioxane, THF, DMF, toluene, NMP or xylene.
  • the reaction is typically performed under conventional or microwave heating in the presence of an acid such as HCl or p-toluenesulfonic acid or in the presence of base such as a non-nucleophilic base such as triethylamine or diisopropylethylamine, or an inorganic base such as potassium carbonate or sodium carbonate. Alternately the reaction can be carried out without solvent.
  • an acid such as HCl or p-toluenesulfonic acid
  • base such as a non-nucleophilic base such as triethylamine or diisopropylethylamine, or an inorganic base such as potassium carbonate or sodium carbonate.
  • base such as a non-nucleophilic base such as triethylamine or diisopropylethylamine, or an inorganic base such as potassium carbonate or sodium carbonate.
  • the reaction can be carried out without solvent.
  • the amine substituent may be introduced through a transition metal catalysed amination reaction.
  • Typical catalysts/ligands for such transformations include Pd(OAc) 2 /P(t-Bu) 3 , Pd 2 (dba) 3 /BINAP and Pd(OAc) 2 /BINAP.
  • These reactions are typically carried out in solvents such as toluene or dioxane, in the presence of bases such as caesium carbonate or sodium or potassium tert-butoxide at temperatures ranging from room temperature to reflux (e.g. Hartwig, J.F., Angew. Chem. Int. Ed. 1998,37,2046 ).
  • the amines employed in the first step of the synthesis of these compounds are obtained commercially or are prepared using methods well known to those skilled in the art.
  • the second step of the process typically begins with a cross-coupling reaction between the monohalogenated derivative obtained above and a suitably functionalised coupling partner.
  • Typical coupling partners are organoboronic acids or esters (Suzuki coupling: see for example Miyaura, N. and Suzuki, Chem Rev. 1995, 95 2457 ), organostannanes (Stille coupling: see for example Stille, J.K., Angew. Chem., Int. Ed. Engl., 1986, 25, 508 ), Grignard reagents (Kumada coupling: Kumada, M.; Tamao, K.; Sumitani, K. Org. Synth. 1988, Coll.
  • Suzuki coupling is the preferred coupling method and is typically performed in a solvent such as DME, THF, DMF, ethanol, propanol, toluene, acetonitrile or 1,4-dioxane, with or without added water, in the presence of a base such as sodium or potassium carbonate, lithium hydroxide, caesium carbonate, sodium hydroxide, potassium fluoride or potassium phosphate.
  • a base such as sodium or potassium carbonate, lithium hydroxide, caesium carbonate, sodium hydroxide, potassium fluoride or potassium phosphate.
  • the reaction may be carried out at elevated temperatures and the palladium catalyst employed may be selected from Pd(PPh 3 ) 4 , Pd(OAc) 2 , [PdCl 2 (dppf], Pd 2 (dba) 3 /P(t-Bu) 3 .
  • reaction step may be further derivatised using techniques known to those skilled in the art.
  • derivatisation of the mono-halo intermediate may be undertaken prior to reaction of the second halo substituent.
  • Those skilled in the art will appreciate that the order of the reactions described for the syntheses above may be changed in certain circumstances and that certain functionalities may need to be derivatised (i.e. protected) in certain instances for the reactions described above to proceed with reasonable yield and efficiency.
  • protecting functionality are well-known to those skilled in the art and are described for example in Greene ( Greene, T., Wuts, P. (1999) Protective Groups in Organic Synthesis. Wiley-Interscience; 3rd editi on.).
  • the leaving group may be any suitable known type such as those disclosed in J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure” 4th Edition, pp 352-357, John Wiley & Sons, New York, 1992 .
  • the leaving group is halogen, more preferably chlorine.
  • the compounds of formula I have activity against protein kinases, particularly the JAK kinases or aurora kinases and most particularly selective activity against JAK1, JAK2, JAK3 or TYK2 kinases or combinations thereof.
  • a JAK2 inhibitor is any compound that selectively inhibits the activity of JAK2.
  • a JAK3 inhibitor is any compound that selectively inhibits the activity of JAK3.
  • a JAK1/JAK2 selective inhibitor is any compound that selectively inhibits both JAK1 and JAK2.
  • One activity of both JAK2 and JAK3 is to phosphorylate a STAT protein. Therefore an example of an effect of a JAK2 or JAK3 inhibitor is to decrease the phosphorylation of one or more STAT proteins.
  • the inhibitor may inhibit the phosphorylated form of JAK2 or JAK3 or the non-phosphorylated form of JAK2 or JAK3.
  • a PTK catalyses the transfer of a phosphate group from a molecule of ATP to a tyrosine residue located on a protein substrate.
  • the inhibitors known in the art are usually competitive with either the ATP or the protein substrate of the kinase (Levitzki 2000). Since the concentration of ATP in a cell is normally very high (millimolar), compounds that are competitive with ATP may lack in vivo activity since it is unlikely that said compounds can reach the concentrations within the cell that are necessary to displace the ATP from its binding site.
  • compositions comprising at least one of the compounds of the formula I and a pharmaceutically acceptable carrier.
  • the carrier must be "pharmaceutically acceptable” means that it is compatible with the other ingredients of the composition and is not deleterious to a subject.
  • the compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavours, etc.) according to techniques such as those well known in the art of pharmaceutical formulation (See, for example, Remington: The Science and Practice of Pharmacy, 21st Ed., 2005, Lippincott Williams & Wilkins ).
  • the compounds of the invention may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, intra(trans)dermal, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray or insufflation; topically, such as in the form of a cream or ointment ocularly in the form of a solution or suspension; vaginally in the form of pessaries, tampons or creams; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents.
  • parenterally such as by subcutaneous, intravenous, intramuscular, intra(trans)dermal, or intracisternal injection or infusion
  • the compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.
  • compositions for the administration of the compounds of the invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. These methods generally include the step of bringing the compound of formula I into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the compound of formula I into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • compositions containing the compound of formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents such as sweetening agents, flavouring agents, colouring agents and preserving agents, e.g. to provide pharmaceutically stable and palatable preparations.
  • Tablets contain the compound of formula I in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the compound of formula I is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the compound of formula I is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoole
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the compound of formula I in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the compound of formula I in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, sorbitol, sorbitol, gly
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectable formulations.
  • the active compound may be administered by any of the methods and formulations employed in the art for administration to the respiratory tract.
  • the active compound may be administered in the form of a solution or a suspension or as a dry powder.
  • Solutions and suspensions will generally be aqueous, for example prepared from water alone (for example sterile or pyrogen-free water) or water and a physiologically acceptable co-solvent (for example ethanol, propylene glycol or polyethylene glycols such as PEG 400).
  • a physiologically acceptable co-solvent for example ethanol, propylene glycol or polyethylene glycols such as PEG 400.
  • Such solutions or suspensions may additionally contain other excipients for example preservatives (such as benzalkonium chloride), solubilising agents/surfactants such as polysorbates (eg. Tween 80, Span 80, benzalkonium chloride), buffering agents, isotonicity-adjusting agents (for example sodium chloride), absorption enhancers and viscosity enhancers.
  • Suspensions may additionally contain suspending agents (for example microcrystalline cellulose and carboxymethyl cellulose sodium).
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the formulations may be provided in single or multidose form. In the latter case a means of dose metering is desirably provided.
  • a dropper or pipette this may be achieved by the subject administering an appropriate, predetermined volume of the solution or suspension.
  • a spray this may be achieved for example by means of a metering atomising spray pump.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the compound is provided in a pressurised pack with a suitable propellant, such as a chlorofluorocarbon (CFC), for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant such as a chlorofluorocarbon (CFC)
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of active compound may be controlled by provision of a metered valve.
  • the active compound may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • PVP polyvinylpyrrolidine
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form, for example in capsules or cartridges of eg. gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the active compound will generally have a small particle size, for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronisation.
  • formulations adapted to give sustained release of the active compound may be employed.
  • the active compound may be administered by oral inhalation as a free-flow powder via a "Diskhaler” (trade mark of Glaxo Group Ltd) or a meter dose aerosol inhaler.
  • the compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed.
  • topical application shall include mouthwashes and gargles.
  • the active compound may be in the form of a solution or suspension in a suitable sterile aqueous or non-aqueous vehicle.
  • Additives for instance buffers, preservatives including bactericidal and fungicidal agents, such as phenyl mercuric acetate or nitrate, benzalkonium chloride, or chlorohexidine and thickening agents such as hypromellose may also be included.
  • the compounds of the present invention can also be administered in the form of liposomes.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilisers, preservatives, excipients and the like.
  • the preferred lipids are the phospholipids and phosphatidyl cholines, both natural and synthetic. Methods to form liposomes are known in the art.
  • Efficacy of this class of compounds may be applicable to drug eluting stents.
  • Potential applications of drug eluting stents with these compounds include pulmonary artery stenosis, pulmonary vein stenosis, as well as coronary artery stenosis.
  • Drug eluting stents may also be used in saphenous vein grafts or arterial grafts or conduits.
  • Drug eluting stents that release this class of compounds may also be applicable for treating stenoses of the aorta or peripheral arteries, such as the iliac artery, the femoral artery or the popliteal artery.
  • the compound may be bound to the drug eluting stent by any of various methods known in the field. Examples of such methods include polymers, phosphoryl choline, and ceramics.
  • the compound may also be impregnated into a bioabsorbable stent.
  • the active compounds may also be presented for use in the form of veterinary compositions, which may be prepared, for example, by methods that are conventional in the art.
  • veterinary compositions include those adapted for: oral administration, external application, for example drenches (e.g. aqueous or non-aqueous solutions or suspensions); tablets or boluses; powders, granules or pellets for admixture with feed stuffs; pastes for application to the tongue; parenteral administration for example by subcutaneous, intramuscular or intravenous injection, e.g. as a sterile solution or suspension; or (when appropriate) by intramammary injection where a suspension or solution is introduced in the udder via the teat; topical applications, e.g. as a cream, ointment or spray applied to the skin; or rectally or intravaginally, e.g. as a pessary, cream or foam.
  • drenches e.g. aqueous or non-aqueous solutions or
  • compositions and uses of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
  • Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles.
  • the combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.
  • Examples of other therapeutic agents include the following: endothelin receptor antagonists (eg ambrisentan, bosentan, sitaxsentan), PDE-V inhibitors (eg sildenafil, tadalafil, vardenafil), Calcium channel blockers (eg amlodipine, felodipine, varepamil, diltiazem, menthol), prostacyclin, treprostinil, iloprost, beraprost, nitric oxide, oxygen, heparin, warfarin, diuretics, digoxin, cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such as ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp39
  • the compounds of formula I may be used in the treatment of kinase associated diseases including JAK kinase associated diseases such immunological and inflammatory diseases including organ transplants; hyperproliferative diseases including cancer and myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases.
  • JAK kinase associated diseases such immunological and inflammatory diseases including organ transplants; hyperproliferative diseases including cancer and myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases.
  • treatment means affecting a subject, tissue or cell to obtain a desired pharmacological and/or physiological effect and include: (a) preventing the disease from occurring in a subject that may be predisposed to the disease, but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; or (c) relieving or ameliorating the effects of the disease, i.e., cause regression of the effects of the disease.
  • subject refers to any animal having a disease which requires treatment with the compound of formula I.
  • mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated.
  • the invention can also be practiced in other species, such as avian species (e.g., chickens).
  • administering should be understood to mean providing a compound of the invention to a subject in need of treatment.
  • kinase associated diseases refers to a disorder or disorders that directly or indirectly result from or are aggravated by aberrant kinase activity, in particular JAK or aurora kinase activity and/or which are alleviated by inhibition of one or more of these kinase enzymes.
  • the kinase associated disease state involves one or more of the JAK kinases, JAK1, JAK2, JAK3 or TYK2.
  • the disease involves JAK2 or JAK3 kinase.
  • diseases include, but are not limited to, those listed in the Table below.
  • Involved Cytokines involved JAK Kinase Involved Characteristics Atopy Allergic Asthma, Atopic Dermatitis (Eczema), Allergic Rhinitis, Mast Cells, Eosinophils, T-Cells, B-Cells, IL-4, IL-5, IL-6, IL-7, IL-13 JAK1, JAK2, JAK3, Tyk2 T-cell activation of B-cells followed by IgE mediated activation of resident Mast cells and Eosinophils CMI Allergic Contact Dermatitis, hypersensitivity pneumonitis T-cells, B-cells, macrophages, neutrophils IL-2, IL-4, IL-5, IL-6, IL-10, IFN ⁇ , TNF, IL-7, IL-13, JAK1, JAK2, JAK3, Tyk2 B cell and/or T DH cell activation Macrophage/granuloc yte activation AutoImmune Diseases Multiple
  • immunological and inflammatory disease refers to an immunological, inflammatory or autoimmune disease, including but not limited to rheumatoid arthritis, polyarthritis, rheumatoid spondylitis, osteoarthritis, gout, asthma, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease, cystic fibrosis, inflammatory bowl disease, irritable bowl syndrome, mucous colitis, ulcerative colitis, diabrotic colitis, Crohn's disease, autoimmune thyroid disorders , gastritis, esophagitis, hepatitis, pancreatitis, nephritis, psoriasis, eczema, acne vulgaris, dermatitis, hives, multiple sclerosis, Alzheimer's disease, Lou Gehrig's disease, Paget's disease, sepsis, conjunctivitis, neranl catarrh, chronic arthrorheumatism,
  • hypoproliferative diseases includes cancer and myeloproliferative disease states such as cellular-proliferative disease states, including but not limited to: Cardiac : sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung : bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hanlartoma, inesothelioma; Gastrointestinal : esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma
  • vascular diseases refers to diseases including but not limited to cardiovascular diseases, hypertension, hypertrophy, hypercholesterolemia, hyperlipidemia, thrombotic disorders, stroke, Raynaud's phenomenon, POEMS syndrome, angina, ischemia, migraine, peripheral arterial disease, heart failure, restenosis, atherosclerosis, left ventricular hypertrophy, myocardial infarction, ischemic diseases of heart, kidney, liver and brain, and pulmonary arterial hypertension.
  • Preferred diseases for JAK2 selective inhibitors include immunological and inflammatory diseases such as auto-immune diseases for example atopic dermatitis, asthma, rheumatoid arthritis, Crohn's disease, psoriasis, Crouzon syndrome, achondroplasia, systemic lupus erythematosus, scleroderma, mixed connective tissue disease, vasculitis, thanatophoric dysplasia and diabetes; hyperproliferative disorders such as cancer for example prostate cancer, colon cancer, breast cancer, gastric cancer, liver cancer such as hepatoma, lung cancer, head and neck cancer such as glioma, skin cancer such as metastatic melanoma, leukemia, lymphoma, multiple myeloma and myleoproliferative diseases such as polycythemia vera, myelofibrosis, thrombocythemia, essential thrombocythemia (ET), agnoneic myeloid metaplasia (
  • Preferred diseases for compounds which selectively inhibit both JAK1 and JAK2 are hyperproliferative diseases such as cancer for example prostate cancer, colon cancer, breast cancer, gastric cancer, liver cancer such as hepatoma, lung cancer, head and neck cancer such as glioma, skin cancer such as metastatic melanoma, leukemia, lymphoma and multiple myeloma.
  • hyperproliferative diseases such as cancer for example prostate cancer, colon cancer, breast cancer, gastric cancer, liver cancer such as hepatoma, lung cancer, head and neck cancer such as glioma, skin cancer such as metastatic melanoma, leukemia, lymphoma and multiple myeloma.
  • Preferred diseases for selective inhibitors of JAK3 are immunological and inflammatory diseases such as systemic lupus erythematosus, mixed connective tissue disease, scleroderma, multiple sclerosis, autoimmune neuritis, rheumatoid arthritis, psoriasis, insulin resistance, Type I diabetes and complications from diabetes, metabolic syndrome, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, and other indications where immunosuppression may be desirable such as organ transplants.
  • specific inhibitors of JAK3 may find application for therapeutic treatments for hyperproliferative diseases such as leukaemia and lymphoma where JAK3 is hyperactivated.
  • terapéuticaally effective amount refers to the amount of the compound of formula I that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.
  • compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient.
  • the dosage may be selected, for example to any dose within any of these ranges, for therapeutic efficacy and/or symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds will preferably be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • the compounds of the invention may be prepared by methods well known to those skilled in the art, and as described in the synthetic and experimental procedures shown below for selected compounds.
  • Methyl-3-amino-2-thiophenecarboxylate (20g, 127mmol) and urea (44g, 732mmol) were heated for 2h at 200°C.
  • the solids obtained were dissolved in 5% aq. NaOH (500mL) and the yellow solution filtered.
  • the basic solution was acidified to pH 5.5 by dropwise addition of 2M HCl and the precipitate collected by filtration to afford the product as a cream/white solid (19.7g, 92%).
  • N-[3-(2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)phenyl]-methanesulfonamide 100 mg, 0.30 mmol, 1.0 eq.
  • NMP 1.2 ml
  • 4-morpholinoaniline 74 mg, 0.48 mmol, 1.4 eq.
  • N,N-diisopropylethylamine 0.132 ml, 0.75 mmol, 2.5 eq.
  • the mixture was heated in a microwave reactor at 240°C for 35 min. An aliquot was then taken and analysed by LCMS.
  • Compound 32 was prepared using the procedures reported above.
  • the HPLC conditions were one of the following: (a) Column: XTerra MS C 18 , 3.5 micron, 2.1 x 50 mm Flow rate : 0.25 mL/min Solvent Gradient: Time % MilliQ water % ACN Curve 0 90 10 1 5 0 100 6 6 0 100 6 7 90 10 6 10 90 10 6 (b) Column: XTerra MS C 18 , 3.5 micron, 2.1 x 50 mm Flow rate : 0.25 mL/min Solvent Gradient: Time % MilliQ water % ACN 0.5% formic acid (aq) Curve 0 90 0 10 1 0.5 90 0 10 6 5.5 0 90 10 6 7.5 0 90 10 6 8.5 90 0 10 6 11.5 90 0 10 6
  • JAK kinase domains were produced using the following procedures:
  • the kinase domain of human JAK1 was amplified from U937mRNA using the polymerase chain reaction with the following primers:
  • the JAK1 PCR products were cloned into the pDest20 destination vector (Gibco).
  • the JAK1 plasmid was then transformed into competent DH10Bac cells (Gibco), and the recombinant baculovirus was prepared via Sf9 insect cell transfection.
  • the kinase domain of human JAK2 was amplified from U937mRNA using the polymerase chain reaction with the following primers:
  • the JAK2 PCR products were cloned into the pDest20 destination vector (Gibco).
  • the JAK2 plasmid was then transformed into competent DH10Bac cells (Gibco), and the recombinant baculovirus was prepared via Sf9 insect cell transfection.
  • the kinase domain of human JAK3 was amplified from U937mRNA using the polymerase chain reaction with the following primers:
  • the JAK3 PCR products were cloned into the pDest20 destination expression vector (Gibco).
  • the JAK3 plasmid was then transformed into competent DH10Bac cells (Gibco), and the recombinant baculovirus was prepared via Sf9 insect cell transfection.
  • Baculovirus preparations from each of the JAK family members were infected into one litre of Sf9 ( Spodoptera frugiperda ) cells (Invitrogen) grown in SF900II serum free medium (Invitrogen) to a cell density of approximately 2 x 10 6 cells/ml. Cells were infected with virus at a cell culture to virus stock ratio of 20:1.Cells were harvested and lysed 48 hours post infection. The GST-tagged JAK kinase domains were purified by affinity chromatography on a GSH agarose column (Scientifix).
  • Kinase assays were performed in 384 well Optiplates (Packard) using an Alphascreen Protein Tyrosine KinaseP100 detection kit
  • the compounds were preincubated with affinity purified PTK domain in the presence of phosphotyrosine assay buffer (10mM HEPES, pH 7.5, 100mM MgCl 2 , 25mM NaCl, 200mM sodium vanadate and 0.1% Tween 20) for 20 minutes.
  • the compounds were then incubated with substrate in the presence of either 80 or 625um ATP for 60 or 90 minutes.
  • the substrate used was either susbtrate-1 with the sequence biotin-EGPWLEEEEEAYGWMDF-NH 2 [SEQ. ID. NO.
  • the coding region encompassing nucleotides 1-487 of TEL was amplified by PCR using the oligonucleotides 5TEL (5'-GGA GGA TCC TGA TCT CTC TCG CTG TGA GAC-3') [SEQ ID NO 14] and 3TEL (5'-AGGC GTC GAC TTC TTC TTC ATG GTT CTG-3') [SEQ ID NO 15] and U937 mRNA as a template.
  • a BamHI restriction site was incorporated into the 5TEL primer, and a Sal I restriction site was incorporated into the 3TEL primer.
  • JAK2 The regions encompassing the kinase domain of JAK2 (nucleotides 2994-3914; JAK2F 5'-ACGC GTC GAC GGT GCC TTT GAA GAC CGG GAT-3' [SEQ ID NO 16]; JAK2R 5'-ATA GTT TAG CGG CCG CTC AGA ATG AAG GTC ATT T-3') [SEQ ID NO 17] and JAK3 (nucleotides 2520-3469; JAK3F 5'-GAA GTC GAC TAT GCC TGC CAA GAC CCC ACG ATC TT-3') [SEQ ID NO 18] were generated by PCR using Taq DNA polymerase (Gibco/BRL) and U937 mRNA as a template.
  • a Sal I restriction site was incorporated into the forward primer of JAK2 and JAK3, a Not I site was incorporated into the JAK2 reverse primer and a Xba I site was added to the reverse primer of JAK3.
  • a TEL/Jak2 fusion was generated by digestion of the TELPCR product with BamH I/Sal I restriction enzymes, digestion of the JAK2 PCR product with Sal I/Not I restriction enzymes, followed by ligation and subcloning of the ligation product into the mammalian expression Vector pTRE 2 (Clontech), which was prepared by digestion with BamH I- Not I restriction enzymes, to give the the TEL/Jak2 fusion plasmid pTELJAK2.
  • the TEL/Jak3 fusion was prepared by ligation of the JAK3 Sal I/Not I cleaved kinase domain PCR product with the BamH I/Sal I restriction digested TEL product, followed by ligation of the ligation product into the BamH I/Not I digested pTRE2, to give the TEL/Jak3 fusion plasmid pTELJAK3.
  • the growth factor dependant myelomonocytic cell line BaF3 bearing the pTET-off plasmid (Clontech) was transfected with either pTELJAK2 or pTELJAK3, and the transfected cells were selected for growth-factor independent cell growth.
  • the BaF3 wild-type cells were cultured in DMEM containing 10% FCS, 10% WEHI 3B conditioned medium.
  • the BaF3 TELJAK cells (BafT_J2 or BafT_J2) were cultured in DMEM 10% Tet-System Approved FBS (without WEHI 3B conditioned medium).
  • Cell suspensions were prepared by harvesting cells from culture. (the cells used in this test were in late log phase growth with high viability.) Cells were diluted in the appropriate growth medium, as described above, to 1.1 x final concentration (from 50,000 cell/mL to 200,000 cell/mL, depending on cell line).
  • Models could be human tumor xenografts models in immuno-deficient mice, from human tumor cell lines or preferably from primary or metastatic human tumors. Other models might be human tumor xenografts grown in orthotopic sites, models of disseminated disease and transgenic or labeled tumors models. Models could also include surgical resection of primary tumor and evaluation of metastatic disease.
  • Models could be selected to ensure that the molecular drug targeted is expressed.
  • tumors displaying deregulation of the JAK/STAT pathway include prostate carcinoma, breast cancer, colon carcinoma, including leukemia, lymphoma, myeloma, ovarian tumors, melanoma, lung carcinoma, glioma, renal-cell tumors.
  • Efficacy can be measured in these models by various outcomes depending on tumor type (solid, leukemia or metastatic) and might include measure of tumor onset, tumor growth rate, tumor burden, tumor growth delay, tumor cell kill, incidence of metastasis, imaging of tumor and invasiveness/metastasis by various approaches including labeled cells or reagents, survival, angiogenesis, histopathology.
  • the in vivo animal efficacy models might also be used for determination of the additivity or synergy of the effect of the compounds in combination with other drugs,
  • RA Rheumatoid arthritis
  • AIA Adjuvant-induced arthritis
  • AIA is also a disease inducible by autologous antigen.
  • CFA Complete Freund's Adjuvant
  • the mid-forpaw, the wrist, the joints of the fingers, the midfoot, the ankle and the joints of the digits are scored giving a maximum clinicl score of 48 per rat.
  • the animals are sacrificed on day 17 and the hindpaws are amputated and fixed in 7.4% formalin.
  • the limbs are sectioned in a mid-sagittal plane, stained by eosin and hematoxylin and examined microscopically for pannus formation (cartilage and bone erosion and destruction), vascularity (blood vessel formation by CD31 staining) and mononuclear cell infiltration (T,B and macrophages).
  • mice that bear H-2 q MHC haplotype are used as they are more susceptible to CIA.
  • heterologous collagen is used as they are more immunogenic/arthritogenic tha homologous type II collagen.
  • the emulsion (0.1ml) is injected into the tail of each mouse approximately 1-2 cm from the base. A whitish bolus beneath the dermis should be visible.
  • a type II collagen booster (200 ⁇ g per mouse) is given intraperitoneally in PBS on day 21.
  • CIA-susceptible mice generally develop arthritis 4-5 weeks after initial priming. Fully developed arthritis including red and swollen paws, can be observed 3-5 days after the onset and active inflammatory arthritis persists more than 3-4 weeks. Although inflammation will eventually subside, joint damage as seen as ankylosis is permanent.
  • Assessment of CIA symptoms is essentially similar to the AIA model in which clinical signs is assigned clinical score (0-4) based on the severity of the disease. Histological measurements can also be performed on formalin-fixed joints to assess erosin, cellular infiltrates and hyperplasia.
  • mice can be used as administration of anti-type II collagen mAB cocktail bypasses the requirement for the host's generation of autoantibodies to type II collagen thus arthritis can be induced in mice that do not possess CIA-susceptible MHC haplotypes and 3. ease of administration of mAB and LPS by either i.v. and i.p. routes.
  • IBD Inflammmatory Bowel Diseases
  • CD Crohn's disease
  • UC ulcerative colitis
  • mice are sensitized at day 0 with 2 x 50 ⁇ l of 5 mg/ml of dinitrofluobenzene (DNFB) epicutaneously to shaved abdomen and feet on two consecutive days.
  • DNFB dinitrofluobenzene
  • acetone:olive oil 4:1
  • DAS dintrobezene sulphonic acid
  • mice are challenged intracolonically with 50 ⁇ l dintrobezene sulphonic acid (DNS) at 6 mg/ml in 10% ethanol.
  • DNS dintrobezene sulphonic acid
  • Parameters to be measured include suppression of total blood cell number and cell types, mucosal mast cell protease 1 (MMCP-1) in serum, TNF ⁇ level in colon homogenate, stool consistency, vascular permeability and number of colonic patches. Number of neutrophils and mast cells which are indicative of colonic damage and cellular influx will also be assessed by histological and microscopical examinations.
  • Asthma is restricted to human species, but animal models are often used to investigate particular aspects of this human disease.
  • Bronchial biopsies and bronchoalveolar lavage (BAL) fluid recovered from patients with asthma have been shown to contain an increased number of activated T cells, B cells, eosinophils and mast cells.
  • Many patients with asthma are sensitized and have specific immunoglogulin E (IgE) antibodies to one or more inhalant allergens. Atopy is, considered to be a major cause of asthma.
  • IgE immunoglogulin E
  • Th2 T-helper 2 cell
  • mice are sensitized by itraperitoneal (ip) injection of ovalbumin (OVA), often together with a Th2 skewed adjuvant, such as alum.
  • OVA ovalbumin
  • C57/BL6 mice are actively sensitized on day 0 by ip injection of 10 ⁇ g of OVA absorbed onto 1 mg of alum. From day 14-21 the mice are exposed daily to aerosolized OVA over a 30 minute period. On day 22, airway inflammation is apparent.
  • BAL fluid recovered from these animals demonstrate an increase in peri-bronchiolar space consisting of mixed cellular infiltrates of mononuclear cells and eosinophils.
  • OVA-specific IgE antibodies can be demonstrated in the serum of sensitized animals.
  • the mononuclear cell population consists mainly of cells of Th2 phenotype secreting cytokines IL-4 and IL-5.
  • IL-4 promotes isotype switching of B cells towards IgE synthesis and IL-5 influences the production, maturation and activation of eosinophils.

Claims (13)

  1. Composé de formule Ib
    Figure imgb0323
     dans lequel
    Z est NR2 ou S ;
    A et B sont indépendamment absents ou C1-6alkylène substitué ou non substitué où un ou plusieurs atomes de carbone peuvent être éventuellement remplacés par 0, CO, NR2, NR2CO, CONR2, NR2SO2, SO2NR2, S et/ou S(O)n ;
    R1 est choisi indépendamment parmi H, C1-6alkyle substitué ou non substitué, C2-6alcényle substitué ou non substitué, C2-6alcynyle substitué ou non substitué, C1-6alcoxy substitué ou non substitué, OH, halogène, CN, NO2, NR2R3, SO2R3, SO2NR2R3, CF3, OCF3, NR2SO2R3, CO2R3, COSR3, CSR3, COR3, NR2, CSR3, NR2CSR3, CONR2R3, NR2COR3, NR2CONR2R3, SO3R3, C3-8cycloalkyle substitué ou non substitué, aryle substitué ou non substitué et hétérocyclyle substitué ou non substitué ayant jusqu'à 3 hétéroatomes choisis parmi N, 0, S et SO2 ;
    R est choisi indépendamment parmi C1-6alkyle substitué ou non substitué, C2-6alcényle substitué ou non substitué, C2-6alcynyle substitué ou non substitué, C1-6alcoxy substitué ou non substitué, OH, halogène, CN, NO2, CO2R3, CONR2R3, NR2COR3, SO3R3, C3-8cycloalkyle, aryle et hétérocyclyle ayant jusqu'à 3 hétéroatomes choisis parmi N, 0, S et SO2, chacun d'entre eux pouvant être substitué par jusqu'à 3 substituants choisis indépendamment parmi C1-6alkyle substitué ou non substitué, C2-6alcényle substitué ou non substitué, C2-6alcynyle substitué ou non substitué, C1-6alcoxy substitué ou non substitué, OH, OCF3, halogène, CN, NO2, NR2R3, SO2R3, SO2NR2R3, NR2SO2R3, CO2R3, COR3, NR2COR3, R2NHCO2R3, CONR2R3, NR2CONR2R3 et hétérocyclyle substitué ou non substitué ayant jusqu'à 3 hétéroatomes choisis parmi N, 0, S et SO2 ;
    R2 et R3 sont choisis indépendamment parmi H, C1-6alkyle substitué ou non substitué, C2-6alcényle substitué ou non substitué, C2-6alcynyle substitué ou non substitué, C1-6alcoxy substitué ou non substitué, CN, C3-8cycloalkyle substitué ou non substitué, aryle substitué ou non substitué et hétérocyclyle substitué ou non substitué ayant jusqu'à 3 hétéroatomes choisis parmi N, 0, S et SO2 ; et
    m va de 1 à 3 ;
    les sels et/ou les stéréoisomères de celui-ci.
  2. Composé selon la revendication 1, dans lequel A est absent, C1-6alkylène substitué ou non substitué ou C1-6alcoxy divalent substitué ou non substitué et B est absent ou S.
  3. Composé selon la revendication 1 ou 2, dans lequel R est choisi indépendamment parmi halogène, CO2R3, CONR2R3, C3-8cycloalkyle, aryle de 5 ou 6 chaînons et hétérocyclyle de 5 à 8 chaînons ayant jusqu'à 3 hétéroatomes choisis parmi N, 0, S et SO2, chacun d'entre eux pouvant être substitué par jusqu'à 3 substituants choisis indépendamment parmi C1-6alkyle substitué ou non substitué, hétérocyclyle de 5 à 8 chaînons substitué ou non substitué ayant jusqu'à 3 hétéroatomes choisis parmi N, 0, S et SO2, R2OH, R2NHCO2R3, OCF3, C1-6alcoxy substitué ou non substitué, OH, NR2R3, SO2NR2R3, NR2SO2R3, NR2COR3, CONR2R3, NR2CONR2R3, COR3, CO2R3 et/ou SO2R3 où R2 et R3 sont tels que définis selon la revendication 1.
  4. Composé selon l'une quelconque des revendications 1 à 3, dans lequel R est choisi indépendamment parmi phényle non substitué ou substitué par au moins l'un parmi NR2R3, NR2COR3, C1-6alcoxy substitué ou non substitué, hétérocyclyle de 5 à 8 chaînons substitué ou non substitué ayant jusqu'à 3 hétéroatomes choisis parmi N, 0, S et SO2, SO2NR2R3, NR2CONR2R3, NR2SO2R3, R2OH, R2NHCO2R3, OCF3, CONR2R3 ou C1-6alkyle substitué ou non substitué ; hétérocyclyle de 5 à 9 chaînons saturé ou insaturé ayant de 1 à 2 atomes de N non substitué ou substitué par au moins l'un parmi C1-6alcoxy, CO2R3 ou NR2R3 ; et hétérocyclyle de 5 à 9 chaînons saturé ou insaturé ayant de 1 à 2 atomes de 0 non substitué ou substitué par au moins l'un parmi C1-6alcoxy, CO2R3 ou NR2R3.
  5. Composé selon l'une quelconque des revendications 1 à 4, dans lequel R1 est choisi indépendamment parmi H, halogène, C1-6alcényle substitué ou non substitué, C2-6alkyle substitué ou non substitué, C1-6alcoxy substitué ou non substitué, OH, halogène, NO2, NR2R3, NR2COR3, CO2R3, SO2R3, NR2SO2R3, C3-8cycloalkyle substitué ou non substitué, aryle de 5 ou 6 chaînons substitué ou non substitué et hétérocyclyle de 5 à 8 chaînons, saturé ou insaturé, substitué ou non substitué et ayant jusqu'à 3 hétéroatomes choisis parmi N, 0, S et SO2.
  6. Composé selon la revendication 5, dans lequel l'hétérocyclyle de 5 à 8 chaînons, saturé ou insaturé, substitué ou non substitué et ayant jusqu'à 3 hétéroatomes choisis parmi N, 0, S et SO2 est morpholino, thiomorpholino, thiomorpholino-1-oxyde, thiomorpholino-1,1-dioxyde, NR2-pipérazine, 4-hydroxypipéridine, 3-hydroxypyrrolidine, 3-hydroxypyrrole, pipéridine et pyrrolidine.
  7. Composé selon l'une quelconque des revendications 1 à 6, dans lequel l'un parmi B-R et A-R1 est un accepteur de Michael choisi parmi
    Figure imgb0324
    Figure imgb0325
    Figure imgb0326
    Figure imgb0327
     où
    D est 0 ou N ;
    R4 est choisi parmi H et C1-4alkyle substitué ou non substitué ; et
    R5 et R6 sont choisis indépendamment parmi H, C1-4alkyle substitué ou non substitué, C1-4alkylNR8R9, C1-4alkylOR8, aryle substitué ou non substitué, ou peuvent être reliés pour former un cycle de 5 à 8 chaînons substitué ou non substitué contenant éventuellement un ou plusieurs hétéroatomes choisis parmi 0, S, SO2 et NR4 ; R7 est choisi parmi OH, OC1-4alkyle, et NR8R9 ;
    p va de 0 à 4 ; et
    où R8 et R9 sont choisis indépendamment parmi H, C1-4alkyle substitué ou non substitué ou peuvent être reliés pour former un cycle de 3-8 chaînons substitué contenant éventuellement un ou plusieurs hétéroatomes choisis parmi 0, S, SO2 et NR4 ; et
    R10 est choisi parmi H et C1-4alkyle substitué ou non substitué.
  8. Composé selon l'une quelconque des revendications 1 à 7, qui est choisi parmi No Structure No Structure 1
    Figure imgb0328
         54
    Figure imgb0329
         2
    Figure imgb0330
         55
    Figure imgb0331
         3
    Figure imgb0332
         56
    Figure imgb0333
         4
    Figure imgb0334
         57
    Figure imgb0335
         5
    Figure imgb0336
         58
    Figure imgb0337
         8
    Figure imgb0338
         59
    Figure imgb0339
         10
    Figure imgb0340
         60
    Figure imgb0341
         11
    Figure imgb0342
         61
    Figure imgb0343
         12
    Figure imgb0344
         62
    Figure imgb0345
         13
    Figure imgb0346
         63
    Figure imgb0347
         14
    Figure imgb0348
         64
    Figure imgb0349
         15
    Figure imgb0350
         65
    Figure imgb0351
         16
    Figure imgb0352
         66
    Figure imgb0353
         17
    Figure imgb0354
         67
    Figure imgb0355
         18
    Figure imgb0356
         68
    Figure imgb0357
         19
    Figure imgb0358
         69
    Figure imgb0359
         20
    Figure imgb0360
         70
    Figure imgb0361
         21
    Figure imgb0362
         71
    Figure imgb0363
         22
    Figure imgb0364
         72
    Figure imgb0365
         25
    Figure imgb0366
         73
    Figure imgb0367
         26
    Figure imgb0368
         74
    Figure imgb0369
         28
    Figure imgb0370
         75
    Figure imgb0371
         29
    Figure imgb0372
         76
    Figure imgb0373
         30
    Figure imgb0374
         77
    Figure imgb0375
         31
    Figure imgb0376
         78
    Figure imgb0377
         32
    Figure imgb0378
         79
    Figure imgb0379
         33
    Figure imgb0380
         80
    Figure imgb0381
         34
    Figure imgb0382
         81
    Figure imgb0383
         35
    Figure imgb0384
         82
    Figure imgb0385
         36
    Figure imgb0386
         83
    Figure imgb0387
         37
    Figure imgb0388
         84
    Figure imgb0389
         38
    Figure imgb0390
         85
    Figure imgb0391
         39
    Figure imgb0392
         86
    Figure imgb0393
         40
    Figure imgb0394
         87
    Figure imgb0395
         41
    Figure imgb0396
         88
    Figure imgb0397
         42
    Figure imgb0398
         89
    Figure imgb0399
         43
    Figure imgb0400
         90
    Figure imgb0401
         44
    Figure imgb0402
         91
    Figure imgb0403
         45
    Figure imgb0404
         92
    Figure imgb0405
         46
    Figure imgb0406
         93
    Figure imgb0407
         47
    Figure imgb0408
         94
    Figure imgb0409
         48
    Figure imgb0410
         95
    Figure imgb0411
         49
    Figure imgb0412
         96
    Figure imgb0413
         50
    Figure imgb0414
         97
    Figure imgb0415
         51
    Figure imgb0416
         98
    Figure imgb0417
         52
    Figure imgb0418
         99
    Figure imgb0419
         53
    Figure imgb0420
         100
    Figure imgb0421
         101
    Figure imgb0422
  9. Procédé de préparation du composé de formule Ib selon l'une quelconque des revendications 1 à 8, comprenant l'étape de couplage d'un composé de formule II
    Figure imgb0423
     dans laquelle
    Z est tel que défini selon la revendication 1 ; et
    X est un groupement partant,
    R étant tel que défini selon la revendication 1 ci-dessus et un composé de formule III
    Figure imgb0424
     dans laquelle
    A, R1 et m sont tels que définis selon la revendication 1.
  10. Composition pharmaceutique comprenant le composé de formule Ib selon l'une quelconque des revendications 1 à 8 et un véhicule pharmaceutiquement acceptable.
  11. Composé de formule Ib selon l'une quelconque des revendications 1 à 8, ou composition pharmaceutique selon la revendication 10, pour une utilisation dans une méthode de traitement d'une maladie associée aux kinases.
  12. Composé ou composition pharmaceutique pou une utilisation selon la revendication 11, caractérisé(e) en ce que la maladie associée aux kinases est une maladie immunologique et inflammatoire, une maladie hyperproliférative, des maladies virales, une maladie métabolique ou une maladie vasculaire.
  13. Composé de formule Ib selon l'une quelconque des revendications 1 à 8, pour une utilisation dans une méthode d'inhibition d'une kinase dans une cellule.
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US8354408B2 (en) 2013-01-15
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